The objectives of this proposal are four-fold: 1. to establish a model for transplacental carcinogenesis in the Wistar rat using diethylstilbestrol(DES) with comparisons to natural estrogens, 2. to identify the mechanisms for this chemically-induced carcinogenesis due to prenatal exposure, 3. to investigate the effects of postnatal hormone exposure (oral contraceptives) in the exposed female progeny, and 4. to modify the incidence of tumorigenesis in this rat model using modifiers of enzyme function or metabolites of DES. During the past two years, it has become apparent that the Wistar rat is a model for the study of DES carcinogenesis. Utilizing both in vivo and in vitro techniques, the pharmacokinetics of DES have been examined. Both metabolism and apparent covalent binding of DES are found for both maternal and fetal tissues. Similar fetal binding for estradiol has not been observed. Studies are in progress to identify the cellular constituents of this tissue binding (RNA,DNA, histone or non-histone proteins), and how enzyme modifiers, e.g., trichloropropene oxide and antioxidants, may alter the metabolism -binding of DES and potentially the tumor/teratogenic incidence for DES. Both vaginal tumors and reproductive tissue teratogenesis have been observed. It was anticipated that within 6-12 mos., tumors would be evident: however, recent data indicate that the vaginal neoplasia has not been detected in animals less than 12 mos. of age. Neither the teratogenesis (infertility, azoospermia, undescended testes, vaginal calculi, hypospadias) nor the vaginal squamous cell carcinoma were observed in 160 controls of which 64 were greater than 12 mos. A vaginal neoplasia incidence of 8-10% was seen in the greater than 12 mos. DES-exposed female progeny; however, due to the lethal effects of the teratogenic lesions, these numbers are reduced, especially at the higher doses. These lesions did demonstrate a dose-response relationship in the progeny following maternal administration of DES on days 18-19-20 of gestation. The major focus of the supplement is to maintain the rats for the tumor studies. This postnatal hormone study will hopefully identify the potential risk/benefit to this prenatally DES-exposed population.